1. Field of the Invention
This invention relates to a pharmaceutical preparation capable of prolonged releasing a physiologically active substance in a controlled state. The pharmaceutical preparation is, particularly, directed to physiologically active peptides such as calcitonin gene-related peptide (CGRP) and maxadilans (MAXs). The pharmaceutical preparation of the invention is useful as an intracorporeal implantation-type, particularly intrathecal implantation-type physiologically active substance-prolonged releasing preparation.
2. Description of Related Art
Prolonged releasing (hereinafter, the same as gradually or delayed releasing) preparations, wherein when the drugs or physiologically active substances are administered into living bodies, elution of the drugs in the living bodies is controlled and their absorption is adjusted, have been investigated from long ago. For example, a method which comprises coating drugs with various coats, a method which comprises incorporating drugs into matrices of waxes or macromolecules, etc. have been known.
However, when intrathecal diseases are treated, in the case of intravenous administration of physiologically active substances, migration of these physiologically active substances into the brains is prevented by the blood brain barriers. As a method for direct administration of a physiologically active substance into brains, there is a method which comprises seating a catheter at the time of the operation and gradually supplying the drug into the brain, but since the apparatus is expensive and in addition there is a large danger of infection, it is hard to say that the method is a reliable method. For example, in delayed cerebral vasospasm occurring after subarachnoid hemorrhage, the pathosis is retardingly manifested and moreover is lasting, and thus a method which comprises inserting a catheter for administration of drugs and a method which comprises continuously administering a drug into the vein are used. However, it is the present state of things that a method for obtaining sure therapeutic effects has not yet been developed.
When one's eyes are turned to physiologically active peptides, particularly calcitonin gene-related peptide (CGRP) and maxadilans (MAXs) about which the present inventors have contemplated development of pharmaceutical preparations effective for various diseases, prolonged releasing pharmaceutical preparations for active substances specifically effective in relation to targeted diseases have not been proposed. When CGRP and maxadilans are specifically taken up, these are extremely interesting as proteins capable of inducing vasodilative and temporary immune suppression in mammals, as disclosed in E. A. Lerner et al., International Publication No. WO 91/00293, but after the report of Lerner et al., prolonged releasing pharmaceutical preparations therefor have not been proposed.
In this connection, the "maxadilans" were described in the above publication as proteins derived from the salivary gland lysate of a sand fly Lutzomyia longipalpis, and, thereafter, named "maxadilans" by them (for example, J. Biol. Chem., vol. 267, 1062-1066, 1992). Lerner et al. exhibit, in the just above literature, through expression of recombinant maxadilans, that the analogues of maxadilan disclosed in WO 91/00293 also have a vasodilative activity. Other maxadilan analogues having a vasodilative activity are disclosed in M. Ohnuma, E. A. Lerner et al., Peptide Chemistry 1993: Y. Okada (Ed.), 145-148.
As an interesting report from the aspect of the pharmacological actions of CGRP, H. Shimizu et al., Nou Shinkei Geka (Neurosurgery), 22(2): 131-139, 1994 discloses that when subarachnoid hemorrhage models of rabbits are used, and portions of an aseptic solution of CGRP (human alpha CGRP: Bachem Feinchemikalien, AG, Budendorf, Switzerland) are injected into the cisterna magnas of the animals, respectively, dilation effects on the contracted blood vessels are obtained.
However, this method is not always satisfactory in the effects of prophylaxis or treatment of cerebral vasospasm where the pathosis is retardingly manifested as stated above, and moreover, it is necessary to continue to strictly monitor the injection of the aqueous solution of the physiologically active substance into the cisterna magna, since said injection is very dangerous, during the injection operation.
Thus, the object of this invention lies in providing a pharmaceutical preparation effective for prophylaxis or treatment of, especially cerebral vasospasm, and a method therefor.